Clinical practice guidelines support home-based exercise for patients with peripheral artery dise... more Clinical practice guidelines support home-based exercise for patients with peripheral artery disease (PAD), but no randomized trials have tested whether an exercise intervention without periodic medical center visits improves walking performance. To determine whether a home-based exercise intervention consisting of a wearable activity monitor and telephone coaching improves walking ability over 9 months in patients with PAD. Randomized clinical trial conducted at 3 US medical centers. Patients with PAD were randomized between June 18, 2015, and April 4, 2017, to home-based exercise vs usual care for 9 months. Final follow-up was on December 5, 2017. The exercise intervention group (n = 99) received 4 weekly medical center visits during the first month followed by 8 months of a wearable activity monitor and telephone coaching. The usual care group (n = 101) received no onsite sessions, active exercise, or coaching intervention. The primary outcome was change in 6-minute walk distance...
Unraveling the complexity of aging is crucial for understanding its mechanisms and its role as a ... more Unraveling the complexity of aging is crucial for understanding its mechanisms and its role as a risk factor for most chronic conditions. Advancements marked by genome-wide association studies (GWASs) have sparked interest in gene cataloguing in the context of aging and age-related conditions. Here, we used GWAS to explore whether single nucleotide polymorphisms (SNPs) were associated with functional and anthropometric parameters in a cohort of old community-dwellers enrolled in the ilSIRENTE study. Analyses were carried out in men and women aged 80+ years enrolled in the ilSIRENTE study (n = 286) and replicated in the inCHIANTI study (n = 1055). Genotyping was accomplished on Infinium Human610-QUAD version 1. In the ilSIRENTE population, genetic variants in ZNF295 and C2CD2 (rs928874 and rs1788355) on chromosome 21q22.3, were significantly associated with the 4-meter gait speed (rs928874, p = 5.61 × 10; rs1788355, p = 5.73 × 10). This association was not replicated in the inCHIANTI...
To derive lean mass cutpoints based on a less-conservative Foundation for the National Institutes... more To derive lean mass cutpoints based on a less-conservative Foundation for the National Institutes of Health (FNIH) Sarcopenia Project Weakness cutpoint for grip strength (WeakI ) and to assess their agreement with European Working Group on Sarcopenia in Older People (EWGSOP) and prediction of incident slow walking and mortality. Longitudinal analysis. Baltimore Longitudinal Study of Aging. Individuals aged 65 and older (287 men, 258 women) with 2 to 10 years of follow-up. Weakness was determined according to handgrip strength using a hand dynamometer, appendicular lean mass (ALM) using dual-energy X-ray absorptiometry, and walking speed according to 6-m usual pace walk speed. Analyses were performed using classification and regression tree analysis, Cohen's kappa, and Cox models. Cutpoints derived from WeakI for ALM (ALMI ) were less than 21.4 kg in men and less than 14.1 kg in women and for ALM adjusted for body mass index (ALM/BMII ) were less than 0.725 in men and less than 0...
The apolipoprotein E (APOE) Ɛ4 allele increases Alzheimer's disease (AD) risk and has been li... more The apolipoprotein E (APOE) Ɛ4 allele increases Alzheimer's disease (AD) risk and has been linked to a greater risk of sleep-disordered breathing. We investigated the association of APOE genotype with non-respiratory sleep parameters. We studied 1,264 cognitively normal participants in the Baltimore Longitudinal Study of Aging (mean = 57.5±16.1 years, range 19.9-92.0, 48.2% women, 19.8% African American) with APOE genotyping and self-reported sleep duration (≥9, 7 or 8, ≤6 hours), difficulty falling/staying asleep, and napping. We compared Ɛ4 carriers with all non-carriers and compared persons at reduced (Ɛ2/Ɛ2 or Ɛ2/Ɛ3) or elevated AD risk (≥1 Ɛ4 allele) with those neutral for AD risk (Ɛ3/Ɛ3). In fully adjusted models, those with ≥1 Ɛ4 allele had a greater odds of being in a shorter sleep duration category compared to all non-carriers (OR = 1.41, 95% CI 1.06, 1.88) and Ɛ3/Ɛ3 carriers (OR = 1.43, 95% CI 1.06, 1.92). Compared to Ɛ3/Ɛ3 carriers, Ɛ2/Ɛ2 or Ɛ2/Ɛ3 carriers had a lower...
Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, pot... more Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter th...
Skeletal muscle mitochondrial oxidative capacity declines with age and negatively affects walking... more Skeletal muscle mitochondrial oxidative capacity declines with age and negatively affects walking performance, but the mechanism for this association is not fully clear. We tested the hypothesis that impaired oxidative capacity affects muscle performance and, through this mechanism, has a negative effect on walking speed. Muscle mitochondrial oxidative capacity was measured by in vivo phosphorus magnetic resonance spectroscopy as the postexercise phosphocreatine resynthesis rate, kPCr , in 326 participants (154 men), aged 24-97 years (mean 71), in the Baltimore Longitudinal Study of Aging. Muscle strength and quality were determined by knee extension isokinetic strength, and the ratio of knee extension strength to thigh muscle cross-sectional area derived from computed topography, respectively. Four walking tasks were evaluated: a usual pace over 6 m and for 150 s, and a rapid pace over 6 m and 400 m. In multivariate linear regression analyses, kPCr was associated with muscle streng...
The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated ... more The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10(-8)) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic...
The journals of gerontology. Series A, Biological sciences and medical sciences, Jan 20, 2017
Anemia is associated with poorer sleep in children, and clinically, anemia is linked to insomnia.... more Anemia is associated with poorer sleep in children, and clinically, anemia is linked to insomnia. However, the association between anemia and insomnia in older adults is understudied. We examined the cross-sectional association between anemia and insomnia in 1,053 adults (71.4 ± 10.6 years) in the Baltimore Longitudinal Study of Aging. Participants were classified as nonanemic, non-iron-deficient anemic, or iron-deficient anemic based on hemoglobin, ferritin, transferrin saturation, and mean cell volume. Insomnia symptoms were evaluated by the Women's Health Initiative Insomnia Rating Scale (WHIIRS). A total score (range 0-20) was generated, and participants were also classified as having 0, 1, or 2+ symptoms. Overall, 10.5% of participants had non-iron-deficient anemia, 0.9% had iron-deficient anemia, and 88.5% had no anemia. Due to its low prevalence, the iron-deficient anemic group was dropped from analyses. In models adjusted for demographics, number of medical conditions, a...
Low-calorie sweetener use for weight control has come under increasing scrutiny as obesity, espec... more Low-calorie sweetener use for weight control has come under increasing scrutiny as obesity, especially abdominal obesity, remain entrenched despite substantial low-calorie sweetener use. We evaluated whether chronic low-calorie sweetener use is a risk factor for abdominal obesity. We used 8268 anthropometric measurements and 3096 food diary records with detailed information on low-calorie sweetener consumption in all food products, from 1454 participants (741 men, 713 women) in the Baltimore Longitudinal Study of Aging collected from 1984 to 2012 with median follow-up of 10 years (range: 0-28 years). At baseline, 785 were low-calorie sweetener non-users (51.7% men) and 669 participants were low-calorie sweetener users (50.1% men). Time-varying low-calorie sweetener use was operationalized as the proportion of visits since baseline at which low-calorie sweetener use was reported. We used marginal structural models to determine the association between baseline and time-varying low-cal...
Men and women exhibit different gait patterns during customary walking and may respond differentl... more Men and women exhibit different gait patterns during customary walking and may respond differently to joint diseases. The present paper aims to identify gait patterns associated with knee-OA separately in men and women. Participants included 144 men and 124 women aged 60 years and older enrolled in the Baltimore Longitudinal Study of Aging (BLSA) who underwent gait testing at a self-selected speed. Both men and women with knee-OA had lower ankle propulsion mechanical work expenditure (MWE;P<.001for both) and higher hip generative MWE (P<.001) compared to non-OA controls. Women with knee-OA had a higher BMI (P=.008), slower gait speed (P=.049), and higher knee frontal-plane absorbing MWE (P=.007) than women without knee-OA. These differences were not observed in men. Understanding sex-specific differences in gait adaptation to knee-OA may inform the development of appropriate strategies for early detection and intervention for knee-OA in men and women.
Background— This study assessed functional performance, calf muscle characteristics, peripheral n... more Background— This study assessed functional performance, calf muscle characteristics, peripheral nerve function, and quality of life in asymptomatic persons with peripheral arterial disease (PAD). Methods and Results— PAD participants (n=465) had an ankle brachial index <0.90. Non-PAD participants (n=292) had an ankle brachial index of 0.90 to 1.30. PAD participants were categorized into leg symptom groups including intermittent claudication (n=215) and always asymptomatic (participants who never experienced exertional leg pain, even during the 6-minute walk; n=72). Calf muscle was measured with computed tomography. Analyses were adjusted for age, sex, race, ankle brachial index, comorbidities, and other confounders. Compared with participants with intermittent claudication, always asymptomatic PAD participants had smaller calf muscle area (4935 versus 5592 mm 2 ; P <0.001), higher calf muscle percent fat (16.10% versus 9.45%; P <0.001), poorer 6-minute walk performance (966...
Formerly known as Obesity Research, Obesity is the official journal of The Obesity Society. Avail... more Formerly known as Obesity Research, Obesity is the official journal of The Obesity Society. Available in print and online, Obesity is dedicated to increasing knowledge, fostering research, and promoting better treatment for people with obesity and their loved ones. Obesity publishes ...
Clinical practice guidelines support home-based exercise for patients with peripheral artery dise... more Clinical practice guidelines support home-based exercise for patients with peripheral artery disease (PAD), but no randomized trials have tested whether an exercise intervention without periodic medical center visits improves walking performance. To determine whether a home-based exercise intervention consisting of a wearable activity monitor and telephone coaching improves walking ability over 9 months in patients with PAD. Randomized clinical trial conducted at 3 US medical centers. Patients with PAD were randomized between June 18, 2015, and April 4, 2017, to home-based exercise vs usual care for 9 months. Final follow-up was on December 5, 2017. The exercise intervention group (n = 99) received 4 weekly medical center visits during the first month followed by 8 months of a wearable activity monitor and telephone coaching. The usual care group (n = 101) received no onsite sessions, active exercise, or coaching intervention. The primary outcome was change in 6-minute walk distance...
Unraveling the complexity of aging is crucial for understanding its mechanisms and its role as a ... more Unraveling the complexity of aging is crucial for understanding its mechanisms and its role as a risk factor for most chronic conditions. Advancements marked by genome-wide association studies (GWASs) have sparked interest in gene cataloguing in the context of aging and age-related conditions. Here, we used GWAS to explore whether single nucleotide polymorphisms (SNPs) were associated with functional and anthropometric parameters in a cohort of old community-dwellers enrolled in the ilSIRENTE study. Analyses were carried out in men and women aged 80+ years enrolled in the ilSIRENTE study (n = 286) and replicated in the inCHIANTI study (n = 1055). Genotyping was accomplished on Infinium Human610-QUAD version 1. In the ilSIRENTE population, genetic variants in ZNF295 and C2CD2 (rs928874 and rs1788355) on chromosome 21q22.3, were significantly associated with the 4-meter gait speed (rs928874, p = 5.61 × 10; rs1788355, p = 5.73 × 10). This association was not replicated in the inCHIANTI...
To derive lean mass cutpoints based on a less-conservative Foundation for the National Institutes... more To derive lean mass cutpoints based on a less-conservative Foundation for the National Institutes of Health (FNIH) Sarcopenia Project Weakness cutpoint for grip strength (WeakI ) and to assess their agreement with European Working Group on Sarcopenia in Older People (EWGSOP) and prediction of incident slow walking and mortality. Longitudinal analysis. Baltimore Longitudinal Study of Aging. Individuals aged 65 and older (287 men, 258 women) with 2 to 10 years of follow-up. Weakness was determined according to handgrip strength using a hand dynamometer, appendicular lean mass (ALM) using dual-energy X-ray absorptiometry, and walking speed according to 6-m usual pace walk speed. Analyses were performed using classification and regression tree analysis, Cohen's kappa, and Cox models. Cutpoints derived from WeakI for ALM (ALMI ) were less than 21.4 kg in men and less than 14.1 kg in women and for ALM adjusted for body mass index (ALM/BMII ) were less than 0.725 in men and less than 0...
The apolipoprotein E (APOE) Ɛ4 allele increases Alzheimer's disease (AD) risk and has been li... more The apolipoprotein E (APOE) Ɛ4 allele increases Alzheimer's disease (AD) risk and has been linked to a greater risk of sleep-disordered breathing. We investigated the association of APOE genotype with non-respiratory sleep parameters. We studied 1,264 cognitively normal participants in the Baltimore Longitudinal Study of Aging (mean = 57.5±16.1 years, range 19.9-92.0, 48.2% women, 19.8% African American) with APOE genotyping and self-reported sleep duration (≥9, 7 or 8, ≤6 hours), difficulty falling/staying asleep, and napping. We compared Ɛ4 carriers with all non-carriers and compared persons at reduced (Ɛ2/Ɛ2 or Ɛ2/Ɛ3) or elevated AD risk (≥1 Ɛ4 allele) with those neutral for AD risk (Ɛ3/Ɛ3). In fully adjusted models, those with ≥1 Ɛ4 allele had a greater odds of being in a shorter sleep duration category compared to all non-carriers (OR = 1.41, 95% CI 1.06, 1.88) and Ɛ3/Ɛ3 carriers (OR = 1.43, 95% CI 1.06, 1.92). Compared to Ɛ3/Ɛ3 carriers, Ɛ2/Ɛ2 or Ɛ2/Ɛ3 carriers had a lower...
Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, pot... more Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter th...
Skeletal muscle mitochondrial oxidative capacity declines with age and negatively affects walking... more Skeletal muscle mitochondrial oxidative capacity declines with age and negatively affects walking performance, but the mechanism for this association is not fully clear. We tested the hypothesis that impaired oxidative capacity affects muscle performance and, through this mechanism, has a negative effect on walking speed. Muscle mitochondrial oxidative capacity was measured by in vivo phosphorus magnetic resonance spectroscopy as the postexercise phosphocreatine resynthesis rate, kPCr , in 326 participants (154 men), aged 24-97 years (mean 71), in the Baltimore Longitudinal Study of Aging. Muscle strength and quality were determined by knee extension isokinetic strength, and the ratio of knee extension strength to thigh muscle cross-sectional area derived from computed topography, respectively. Four walking tasks were evaluated: a usual pace over 6 m and for 150 s, and a rapid pace over 6 m and 400 m. In multivariate linear regression analyses, kPCr was associated with muscle streng...
The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated ... more The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10(-8)) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic...
The journals of gerontology. Series A, Biological sciences and medical sciences, Jan 20, 2017
Anemia is associated with poorer sleep in children, and clinically, anemia is linked to insomnia.... more Anemia is associated with poorer sleep in children, and clinically, anemia is linked to insomnia. However, the association between anemia and insomnia in older adults is understudied. We examined the cross-sectional association between anemia and insomnia in 1,053 adults (71.4 ± 10.6 years) in the Baltimore Longitudinal Study of Aging. Participants were classified as nonanemic, non-iron-deficient anemic, or iron-deficient anemic based on hemoglobin, ferritin, transferrin saturation, and mean cell volume. Insomnia symptoms were evaluated by the Women's Health Initiative Insomnia Rating Scale (WHIIRS). A total score (range 0-20) was generated, and participants were also classified as having 0, 1, or 2+ symptoms. Overall, 10.5% of participants had non-iron-deficient anemia, 0.9% had iron-deficient anemia, and 88.5% had no anemia. Due to its low prevalence, the iron-deficient anemic group was dropped from analyses. In models adjusted for demographics, number of medical conditions, a...
Low-calorie sweetener use for weight control has come under increasing scrutiny as obesity, espec... more Low-calorie sweetener use for weight control has come under increasing scrutiny as obesity, especially abdominal obesity, remain entrenched despite substantial low-calorie sweetener use. We evaluated whether chronic low-calorie sweetener use is a risk factor for abdominal obesity. We used 8268 anthropometric measurements and 3096 food diary records with detailed information on low-calorie sweetener consumption in all food products, from 1454 participants (741 men, 713 women) in the Baltimore Longitudinal Study of Aging collected from 1984 to 2012 with median follow-up of 10 years (range: 0-28 years). At baseline, 785 were low-calorie sweetener non-users (51.7% men) and 669 participants were low-calorie sweetener users (50.1% men). Time-varying low-calorie sweetener use was operationalized as the proportion of visits since baseline at which low-calorie sweetener use was reported. We used marginal structural models to determine the association between baseline and time-varying low-cal...
Men and women exhibit different gait patterns during customary walking and may respond differentl... more Men and women exhibit different gait patterns during customary walking and may respond differently to joint diseases. The present paper aims to identify gait patterns associated with knee-OA separately in men and women. Participants included 144 men and 124 women aged 60 years and older enrolled in the Baltimore Longitudinal Study of Aging (BLSA) who underwent gait testing at a self-selected speed. Both men and women with knee-OA had lower ankle propulsion mechanical work expenditure (MWE;P<.001for both) and higher hip generative MWE (P<.001) compared to non-OA controls. Women with knee-OA had a higher BMI (P=.008), slower gait speed (P=.049), and higher knee frontal-plane absorbing MWE (P=.007) than women without knee-OA. These differences were not observed in men. Understanding sex-specific differences in gait adaptation to knee-OA may inform the development of appropriate strategies for early detection and intervention for knee-OA in men and women.
Background— This study assessed functional performance, calf muscle characteristics, peripheral n... more Background— This study assessed functional performance, calf muscle characteristics, peripheral nerve function, and quality of life in asymptomatic persons with peripheral arterial disease (PAD). Methods and Results— PAD participants (n=465) had an ankle brachial index <0.90. Non-PAD participants (n=292) had an ankle brachial index of 0.90 to 1.30. PAD participants were categorized into leg symptom groups including intermittent claudication (n=215) and always asymptomatic (participants who never experienced exertional leg pain, even during the 6-minute walk; n=72). Calf muscle was measured with computed tomography. Analyses were adjusted for age, sex, race, ankle brachial index, comorbidities, and other confounders. Compared with participants with intermittent claudication, always asymptomatic PAD participants had smaller calf muscle area (4935 versus 5592 mm 2 ; P <0.001), higher calf muscle percent fat (16.10% versus 9.45%; P <0.001), poorer 6-minute walk performance (966...
Formerly known as Obesity Research, Obesity is the official journal of The Obesity Society. Avail... more Formerly known as Obesity Research, Obesity is the official journal of The Obesity Society. Available in print and online, Obesity is dedicated to increasing knowledge, fostering research, and promoting better treatment for people with obesity and their loved ones. Obesity publishes ...
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